The present invention generally relates to multi-well platforms for use in spectroscopic measurements and methods of using such multi-well platforms. Multi-well platforms are particularly useful for fluorescence measurements of chemical or biological samples. The multi-well platforms can be used in automated and integrated systems and methods for rapidly identifying chemicals with biological activity in liquid samples, particularly automated screening of low volume samples for new medicines, agrochemicals, or cosmetics.
A number of multi-well platforms are commercially available for culturing cells or performing chemical or cellular assays. While many of these multi-well platforms offer the desirable features of biocompatibility, ease of manufacture and substantial structural integrity, the inventors of the present invention have generally found that these multi-well platforms, especially plates with polymeric bottoms, suffer from a substantially high degree of fluorescence. The relatively high amount of background fluorescence inherent in commercially available multi-well platforms with polymeric bottoms makes such multi-well platforms generally not suitable for highly sensitive fluorescence measurements associated with many assays.
In the course of miniaturizing and automating screening assays, the inventors of the present invention realized that existing multi-well platforms were generally not suited for assay volumes of a microliter or less. The inventors of the present invention discovered that when existing multi-well platforms were used for such small volumes, the assay became unpredictable and sometimes inoperable. Others have used a variety of multi-well platforms in an attempt to produce a multi-well platform suitable for miniaturization, but none of these multi-well platforms were found by the present inventors to be suitable for their applications. Having discovered this previously unrecognized problem, the inventors of the present invention set out to make a multi-well platform compatible with miniaturized assays, such as fluorescent based assays.
The inventors prepared selection criteria for suitable materials for manufacturing multi-well platforms for such applications. As a key example of the selection criteria, which is more fully described herein, the inventors investigated the spectral properties of various materials, including their fluorescence and transmittance, for compatibility with spectroscopic measurements of chemical and biological events. Such materials would also desirably, but not necessarily depending on the application, have biocompatibility, relative chemical inertness, and sufficient rigidity for the application at hand, and ease of manufacture. The inventors selected a variety of materials for testing based, in part, on the structural features of the materials, which is more fully described herein. The inventors"" search for materials included searching fields not associated with spectroscopic measurements, such as the electronics and audio recording arts. The inventors compared a variety of materials to glass that has relatively minor inherent fluorescence. The inventors realized that fused silica would tend to have less inherent fluorescence than glass.
As described herein the inventors for the first time have developed novel multi-well platforms that offer excellent performance characteristics in fluorescent assays. Such multi-well platforms can be used in conventional 96-well formats or higher density formats, such as less than 864 wells per platform or 864 or more wells per platform. Higher density formats, such as greater than 3,000 wells per multi-well platform, are also part of the invention.
Systems and methods for rapidly identifying chemicals with biological activity in samples, especially small liquid samples, can benefit a number of different fields. For instance, the agrochemical, pharmaceutical, environmental and cosmetic fields all have applications where large numbers of liquid samples containing chemicals are processed. Currently, many such fields use various strategies to reduce processing times, such as simplified chemistry, semi-automation, and robotics. While such strategies may improve the processing time for a particular type of liquid sample, process step or chemical reaction, such methods or apparatuses can seldom integrate the entire process, especially the generation or detection of chemical events in small volumes. Such apparatuses are also often limited in their application, since many of them are designed for, and dedicated to, a particular type of liquid sample or chemical reaction.
In most processes involving liquid samples, as the complexity of the liquid sample processing increases, the process time per sample increases. Although some very simple chemical reactions or liquid processing methods can achieve extremely high throughput rates, such as in the manufacturing of containerized liquids, complicated processing of liquids is typically several orders of magnitude slower. In some instances, the processing of liquid samples, such as in pharmaceutical arts, which usually demands complicated liquid processing for drug discovery, can obtain throughput rates of approximately 3,000 samples per day. This type of processing in general, however, uses liquid sample volumes on the order of 100 to 200 microliters, which often requires relatively large amounts of exotic and expensive reagents, and does not typically incorporate automated access to large stores of liquid reagents.
Consequently, there is a need to provide components, systems and methods for rapidly processing liquid samples at high throughput rates, particularly liquid samples of microliter volumes, one to ten microliters, to identify chemicals with useful activity. The multi-well platform of the present invention addresses these concerns and provides additional benefits as well.